Molecular Dissection of Growth Factor Receptor Signaling

DESCRIPTION (provided by applicant): Dysregulated tyrosine kinase activity is implicated in a large number of human cancers. Several members of the epidermal growth factor receptor family are amplified and overexpressed in human tumors and abrogation of their activity can lead to improved prognosis and survival. Although the mechanisms underlying the mitogenic pathways downstream of receptor tyrosine kinases are quite well understood, little is known about how these proliferative signals are shut off. In a proteomic screen to identify molecules in the EGF receptor pathway, we have previously identified Odin, a novel tyrosine-phosphorylated adapter protein containing PTB, Ankyrin and SAM domains. We have demonstrated that overexpression of Odin leads to inhibition of growth factor-induced signaling and proliferation in fibroblasts. RNAi-based knockdown of Odin ortholog in C. elegans leads to sterility indicating the importance of this evolutionarily conserved molecule. In preliminary studies, we have identified Grb2 as a molecule that interacts with Odin. We hypothesize that Odin acts as a negative regulator of growth factor receptor signaling by binding to Grb2 and disrupting the Grb2/Sos/Ras complex. Based on our preliminary data demonstrating association of Odin with several proteins in an EGF-inducible fashion, we further hypothesize that different domains of Odin participate in the recruitment of this multiprotein complex, which is crucial for Odin function. Finally, we hypothesize that Odin plays a role in transformation of fibroblasts by activated tyrosine kinases and in mammary gland development and tumor formation. The significance of this proposal is that it will allow us to define the biochemical mechanisms that help downregulate growth factor induced signaling as well as elucidate the in vivo relevance of Odin in mammary tissue. A detailed understanding of such inhibitory mechanisms will be crucial for strategies that target intracellular signaling molecules in the treatment of human cancers.